1. Field of the Invention
The present invention relates generally to the fields of biochemical endocrinology and receptor chemistry. More specifically, the present invention relates to novel oxy-sterol ligands for the LXR receptor and uses thereof.
2. Description of the Related Art
All-trans retinoic acid and 9-cis retinoic acid are metabolites of vitamin A that mediate tissue specific expression of target genes. This is accomplished through binding of two classes of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Like other members of the nuclear receptor superfamily, the retinoid receptors transactivate their target genes by binding to specific sites called hormone response elements found within the 5′ regulatory region of the target gene.
The highest affinity hormone response elements for the retinoid receptors, as well as the vitamin D receptor (VDR), thyroid hormone receptors (TRs) and peroxisome proliferative activated receptors (PPARs) have been characterized as direct repeats of the canonical hexad, AGGTCA, separated by one to five nucleotides. RAR, VDR, TR and PPAR preferentially bind to their hormone response elements in vitro as heterodimers complexed with RXR. Reconstitution studies in yeast and RXR gene disruption experiments in mice confirm the function of the RXR heterodimer and suggest that it has an obligatory role in vivo as well as in vitro. Thus, RXRs appear to be essential pleiotropic regulators of several signaling pathways.
In terms of retinoid signaling, two distinct pathways are known, the RXR/RAR heterodimer and RXR homodimer. The RXR/RAR heterodimer mediates all-trans retinoic acid or 9-cis retinoic acid action through its high affinity binding to a direct repeat response element having a spacer of 5 nucleotides, i.e., a DR5 element, and to some extent DR2 elements. Recently, it has been shown that when the RXR/RAR heterodimer is bound to DNA, RXR occupies the 5′ half-site and RAR occupies the 3′ half-site of the DR5 element. In this configuration, RXR is unable to bind ligand and thus functions as a silent partner. The role of RXR as a silent partner is consistent with the finding that other receptors that heterodimerize with RXR do not require 9-cis retinoic acid for their activation.
In the RXR homodimer, RXR acts as its own partner and mediates 9-cis retinoic acid action through binding to DR1 elements. Interestingly, the RXR/RAR heterodimer also binds the DR1 element and does so with higher affinity than the RXR homodimer. The consequence of this binding is that the RXR/RAR heterodimer is a potent repressor of 9-cis retinoic acid activation through the RXR homodimer. These findings suggest that in order for the RXR homodimer to be active, i.e., for RXR to be able to function in vivo as a 9-cis retinoic acid receptor), the ratio of RXR to RAR in a cell must be very high. This may explain why cells that endogenously express RXR and RAR yield significant retinoid responses with DR5 containing reporter genes but do not yield any response with DR1-containing reporter genes, unles RXRs are overexpressed in these cells.
Recently, an orphan member of the nuclear receptor superfamily, named LXRα, in the presence of RXR ligand, e.g., 9-cis retinoic acid, is a potent inducer of transactivation through a distinct retinoid response element. The LXRα response to retinoids is due to the unique interaction of LXRα with endogenous RXR in cells. This interaction permits RXR to work as an active, ligand-binding heterodimeric partner. LXRα has the ability to function as a tissue-specific mediator of a novel retinoid-response pathway.
The prior art is deficient in the lack of the ability to transactivate LXRα in vivo. The prior art is further deficient in the lack of a nuclear receptor signaling pathway for oxysterols and methods to manipulate the use of LXRα as a sensor of cholesterol metabolites. The present invention fulfills this longstanding need and desire in the art.